tbuckley/cabot-search huggingface dataset:
Renin–Angiotensin System Inhibition in Advanced Chronic Kidney Disease
Authors: Sunil Bhandari, Samir Mehta, Arif Khwaja, John G.F. Cleland, Natalie Ives, Elizabeth Brettell, Marie Chadburn, Paul Cockwell
Journal: New England Journal of Medicine (2022)

Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline.In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m2 in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P = 0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22).Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISRCTN number, 62869767.).
SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis
Authors: Dibyendu K. Panda, Xiuying Bai, Yan Zhang, Nicholas A. Stylianesis, Antonis E. Koromilas, Mark L. Lipman, Andrew C. Karaplis
Journal: Journal of Clinical Investigation (2022)

The Hippo pathway nuclear effector Yes-associated protein (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1), driven by ERK1/2 and PI3K/AKT cascades, induced ER proteotoxic stress. To reduce this stress by reprogramming translation, the protein kinase R-like ER kinase-eukaryotic initiation factor 2α (PERK/eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress/ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan impeded these processes. Restoring ER homeostasis and/or interfering with the SKP2-YAP interaction represent potential therapeutic avenues for stemming the progression of renal cystogenesis.
Developmental Deconvolution Suggests New Tumor Biology and a Tool for Predicting Cancer Origin
Authors: Linghua Wang
Journal: Cancer Discovery (2022)

Summary: Defining the developmental origins of cancer can help uncover cellular mechanisms of cancer development and progression and identify effective treatments, but it has been challenging. In this issue of Cancer Discovery, Moiso and colleagues constructed a developmental map of 33 cancer types, based on which they deconvoluted tumors into developmental components and constructed a deep learning classifier capable of high- accuracy tumor type prediction. See related article by Moiso et al., p. 2566 (4) .
Partially Oxidized Alginate as a Biodegradable Carrier for Glucose‐Responsive Insulin Delivery and Islet Cell Replacement Therapy
Authors: Lisa R. Volpatti, Matthew A. Bochenek, Amanda L. Facklam, Delaney M. Burns, Corina MacIsaac, Alexander Morgart, Benjamin Walters, Robert Langer, Daniel G. Anderson
Journal: Advanced Healthcare Materials (2022)

Self-regulated insulin delivery that mimics native pancreas function has been a long-term goal for diabetes therapies. Two approaches towards this goal are glucose-responsive insulin delivery and islet cell transplantation therapy. Here, biodegradable, partially oxidized alginate carriers for glucose-responsive nanoparticles or islet cells are developed. Material composition and formulation are tuned in each of these contexts to enable glycemic control in diabetic mice. For injectable, glucose-responsive insulin delivery, 0.5 mm 2.5% oxidized alginate microgels facilitate repeat dosing and consistently provide 10 days of glycemic control. For islet cell transplantation, 1.5 mm capsules comprised of a blend of unoxidized and 2.5% oxidized alginate maintain cell viability and glycemic control over a period of more than 2 months while reducing the volume of nondegradable material implanted. These data show the potential of these biodegradable carriers for controlled drug and cell delivery for the treatment of diabetes with limited material accumulation in the event of multiple doses.
Advanced serrated polyps as a target of screening: detection rate and positive predictive value within a fecal immunochemical test-based colorectal cancer screening population
Authors: David E. F. W. M. van Toledo, Emilie C. H. Breekveldt, Joep E. G. IJspeert, Anneke J. van Vuuren, Folkert J. van Kemenade, Christian Ramakers, Iris D. Nagtegaal, Monique E. van Leerdam, Manon C. W. Spaander, Iris Lansdorp-Vogelaar, Esther Toes-Zoutendijk, Evelien Dekker
Journal: Endoscopy (2022)

BACKGROUND : Advanced serrated polyps (ASPs) have a comparable risk to advanced adenomas for progression to colorectal cancer (CRC). The yield of most CRC screening programs, however, is based on advanced adenomas and CRC only. We assessed the ASP detection rate, and positive predictive value (PPV) including ASPs in a fecal immunochemical test (FIT)-based screening program. METHODS : We analyzed the findings of follow-up colonoscopies of FIT-positive screenees in the Dutch CRC screening program from 2014 until 2020. Data were retrieved from the national screening and pathology database. An ASP was defined as any serrated polyp of ≥ 10 mm, sessile serrated lesion with dysplasia, or traditional serrated adenoma. The ASP detection rate was defined as the proportion of colonoscopies with ≥ 1 ASP. PPV was originally defined as the proportion of individuals with a CRC or advanced adenoma. The updated PPV definition included CRCs, advanced adenomas, and/or ASPs. RESULTS : 322 882 colonoscopies were included in the analyses. The overall detection rate of ASPs was 5.9 %. ASPs were detected more often in women than men (6.3 % vs. 5.6 %; P < 0.001). ASP detection rates in individuals aged 55-59, 60-64, 65-69, and 70 + were 5.2 %, 6.1 %, 6.1 %, and 5.9 %, respectively (P < 0.001). The PPV for CRCs and advanced adenomas was 41.1 % and increased to 43.8 % when including ASPs. The PPV increase was larger in women than in men (3.2 vs. 2.4 percentage points). CONCLUSIONS : 5.9 % of FIT-positive screenees had ASPs, but half of these were detected in combination with a CRC or advanced adenoma. Therefore, including ASPs results in a small increase in the yield of FIT-based screening.
Smartphone Psychotherapy Reduces Fear of Cancer Recurrence Among Breast Cancer Survivors: A Fully Decentralized Randomized Controlled Clinical Trial (J-SUPPORT 1703 Study)
Authors: Tatsuo Akechi, Takuhiro Yamaguchi, Megumi Uchida, Fuminobu Imai, Kanae Momino, Fujika Katsuki, Naomi Sakurai, Tempei Miyaji, Tomoe Mashiko, Masaru Horikoshi, Toshi A. Furukawa, Akiyo Yoshimura, Shinji Ohno, Natsue Uehiro, Kenji Higaki, Yoshie Hasegawa, Kazuhisa Akahane, Yosuke Uchitomi, Hiroji Iwata
Journal: Journal of Clinical Oncology (2022)

Fear of cancer recurrence (FCR) is a common distressing condition. We investigated the efficacy of smartphone problem-solving therapy and behavioral activation applications in breast cancer survivors.
Antiandrogen Treatment vs Active Surveillance for Patients With Prostate Cancer—Reply
Authors: Neal D. Shore, Matthew R. Cooperberg, Scott A. Tomlins
Journal: JAMA Oncology (2022)

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Nanomaterials for NIR‐II Photoacoustic Imaging
Authors: Shanshan Jiang, Jing Lin, Peng Huang
Journal: Advanced Healthcare Materials (2022)

Compared with the photoacoustic imaging (PAI) in the first near-infrared window (NIR-I, 700-1000 nm), the PAI in the second near-infrared window (NIR-II, 1000-1700 nm) has the advantages of less background noise, deeper tissue penetration, and larger maximum permissible exposure, which has been become a research hotspot. In this review, the recent advances in nanomaterials for NIR-II PAI are summarized, including the advantages of NIR-II PAI and the applications of nanomaterials-based NIR-II PAI in biomedical field. The nanomaterials-based PA contrast agents are classified into three categories, including organic (such as assembled small molecules, conjugated polymers, semiconducting polymers, and phthalocyanines), inorganic (such as metal sulfides, noble metals, carbon nanomaterials, quantum dots, 2D transition metal carbides and nitrides [MXenes], and semimetals), or organic/inorganic hybrid nanomaterials, which are mainly used for imaging and diagnosis of tumor tissues, brain vasculature, inflammation, and other tissues, as well as the monitoring of catalytic reaction processes in vivo. Moreover, the opportunities and challenges of NIR-II PAI are also expounded.
Weight change and clinical outcomes in heart failure with reduced ejection fraction: insights from <scp>EMPEROR‐Reduced</scp>
Authors: Stefan D. Anker, Muhammad Shahzeb Khan, Javed Butler, Anne Pernille Ofstad, Barbara Peil, Egon Pfarr, Wolfram Doehner, Naveed Sattar, Andrew J. S. Coats, Gerasimos Filippatos, João Pedro Ferreira, Faiez Zannad, Stuart Pocock, Milton Packer
Journal: European Journal of Heart Failure (2022)
Revisiting coexisting chromosomal abnormalities in <i>NPM1</i>-mutated AML in light of the revised ELN 2022 classification
Authors: Linus Angenendt, Christoph Röllig, Pau Montesinos, Farhad Ravandi, Gunnar Juliusson, Christian Récher, Raphaël Itzykson, Zdeněk Ráčil, Andrew H. Wei, Christoph Schliemann
Journal: Blood (2022)
Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia
Authors: Xia Xiao, Gillian A. Moschetta, Yang Xu, Allison L. Fisher, Víctor M. Alfaro-Magallanes, Som Dev, Chia-Yu Wang, Jodie L. Babitt
Journal: Blood (2022)
Enhancement of Gene Editing and Base Editing with Therapeutic Ribonucleoproteins through In Vivo Delivery Based on Absorptive Silica Nanoconstruct
Authors: Seongchan Kim, You Kyeong Jeong, Chang Sik Cho, SeokHoon Lee, Chang Ho Sohn, Jeong Hun Kim, Youngdo Jeong, Dong Hyun Jo, Sangsu Bae, Hyojin Lee
Journal: Advanced Healthcare Materials (2022)

Key to the widespread and secure application of genome editing tools is the safe and effective delivery of multiple components of ribonucleoproteins (RNPs) into single cells, which remains a biological barrier to their clinical application. To overcome this issue, a robust RNP delivery platform based on a biocompatible sponge-like silica nanoconstruct (SN) for storing and directly delivering therapeutic RNPs, including Cas9 nuclease RNP (Cas9-RNP) and base editor RNP (BE-RNP) is designed. Compared with commercialized material such as lipid-based methods, up to 50-fold gene deletion and 10-fold base substitution efficiency is obtained with a low off-target efficiency by targeting various cells and genes. In particular, gene correction is successfully induced by SN-based delivery through intravenous injection in an in vivo solid-tumor model and through subretinal injection in mouse eye. Moreover, because of its low toxicity and high biodegradability, SN has negligible effect on cellular function of organs. As the engineered SN can overcome practical challenges associated with therapeutic RNP application, it is strongly expected this platform to be a modular RNPs delivery system, facilitating in vivo gene deletion and editing.
Hydroxyurea for secondary stroke prevention in children with sickle cell anemia in Nigeria: a randomized controlled trial
Authors: Shehu U. Abdullahi, Surayya Sunusi, Mohammed Sani Abba, Saifuddeen Sani, Hauwau Aminu Inuwa, Safiya Gambo, Awwal Gambo, Bilya Musa, Brittany V. Covert Greene, Adetola A. Kassim, Mark Rodeghier, Nafiu Hussaini, Mariana Ciobanu, Muktar H. Aliyu, Lori C. Jordan, Michael R. DeBaun
Journal: Blood (2022)

We tested the hypothesis that fixed oral moderate-dose hydroxyurea (20 mg/kg per day) for initial treatment of secondary stroke prevention results in an 80% relative risk reduction of stroke or death when compared with fixed oral low-dose hydroxyurea (10 mg/kg per day) in a phase 3 double-blind, parallel-group, randomized controlled trial in children with sickle cell anemia (SCA) living in Nigeria. A total of 101 participants were randomly allocated to low-dose (n = 49) and moderate-dose (n = 52) hydroxyurea treatment groups. The median participant follow-up was 1.6 years (interquartile range, 1.0-2.3), with a planned minimum follow-up of 3.0 years. A total of 6 recurrent strokes and 2 deaths vs 5 recurrent strokes and 3 deaths occurred in the low- and moderate-dose groups, respectively. The incidence rate ratio (IRR) of the primary outcome measure of stroke or death in the low- and moderate-dose hydroxyurea treatment groups was 0.98 (95% confidence interval [CI], 0.32-3.00; P = .97). The trial was stopped early owing to no clinical difference in the incidence rates of the primary outcome measure. The incidence rates of recurrent strokes were 7.1 and 6.0 per 100 person-years in the low- and moderate-dose groups, respectively, (IRR, 1.18; 95% CI, 0.30-4.88; P = .74). As a measure of adherence to the oral hydroxyurea therapy, the median percent of returned pills was 3.0% and 2.6% in the low- and moderate-dose groups, respectively. No participant had hydroxyurea therapy stopped for myelosuppression. For children with SCA in low-income settings without access to regular blood transfusion therapy, initial low-dose hydroxyurea is a minimum known efficacious dose for secondary stroke prevention.
C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse
Authors: Li-Xue Yang, Cheng-Tao Zhang, Meng-Ying Yang, Xue-Hong Zhang, Hong-Chen Liu, Chen-Hui Luo, Yue Jiang, Zhang-Man Wang, Zhong-Yin Yang, Zhao-Peng Shi, Yi-Ci Yang, Ruo-Qu Wei, Li Zhou, Jun Mi, Ai-Wu Zhou, Zhi-Rong Yao, Li Xia, Jin-Song Yan, Ying Lu
Journal: Blood (2022)

Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line-derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-globular C1Q receptor recognition and subsequent stimulation of transforming growth factor β1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.
Neuroepithelial Interactions in Cancer
Authors: Gustavo Ayala
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Nerves not only regulate the homeostasis and energetic metabolism of normal epithelial cells but also are critical for cancer, as cancer recapitulates the biology of neural regulation of epithelial tissues. Cancer cells rarely develop in denervated organs, and denervation affects tumorigenesis, in vivo and in humans. Axonogenesis occurs to supply the new malignant epithelial growth with nerves. Neurogenesis happens later, first in ganglia around organs or the spinal column and subsequently through recruitment of neuroblasts from the central nervous system. The hallmark of this stage is regulation of homeostasis and energetic metabolism. Perineural invasion is the most efficient interaction between cancer cells and nerves. The hallmark of this stage is increased proliferation and decreased apoptosis. Finally, carcinoma cells transdifferentiate into a neuronal profile in search of neural independence. The latter is the last stage in neuroepithelial interactions. Treatments for cancer must address the biology of neural regulation of cancer.
Therapeutic activity of GARP:TGF-β1 blockade in murine primary myelofibrosis
Authors: Sara Lecomte, Julien Devreux, Grégoire de Streel, Nicolas van Baren, Violaine Havelange, David Schröder, Noora Vaherto, Christophe Vanhaver, Christophe Vanderaa, Noémie Dupuis, Christian Pecquet, Pierre G. Coulie, Stefan N. Constantinescu, Sophie Lucas
Journal: Blood (2022)

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by the clonal expansion of myeloid cells, notably megakaryocytes (MKs), and an aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-β1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-β1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-β1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-β1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found an increased expression of GARP in the BM and spleen of mice with PMF and tested the therapeutic potential of a monoclonal antibody (mAb) that blocks TGF-β1 activation by GARP-expressing cells. GARP:TGF-β1 blockade reduced not only fibrosis but also the clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-β1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-γ signals in the spleen, were lost upon CD8 T-cell depletion. Our results suggest that the selective blockade of TGF-β1 activation by GARP-expressing Tregs increases a CD8 T-cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.